I. Brachytherapy
Radiation therapy refers to the treatment of diseases with ionizing radiation. Of particular interest is the treatment of neoplastic disease, especially solid, malignant tumors. In radiation therapy, the goal is to destroy the malignant tissue while concomitantly minimizing the exposure of medical personnel to radiation and minimizing radiation damage to other tissue, such as nearby healthy tissue. The recognized method employed for radiation treatment in body cavities (e.g., the throat, bowel or vaginal region, and in regions of the body opened surgically) is brachytherapy, in which one or more radiation sources is brought, controlled by an afterloading device, in a precise and metered manner to the site of treatment in the body. The radiation source is then moved to provide a previously-calculated isodose contour. See, e.g., See, Nath, et al., 1995. Dosimetry of interstitial brachytherapy sources: Recommendations of the AAPM Radiation Therapy Committee Task Group No. 43, Med. Phys. 22: 209–234); Lukas, et al., Intraoperative Radiotherapy with High Dose Afterloading (Flabs Method), in: Intraoperative Radiation Therapy”, Proceedings 4th International Symposium IORT, Schildberg and Kramling, eds., 1992 (Verlag Die Blaue Eule, Essen).
In brachytherapy, there is a relatively short distance (i.e., typically 0.1–5 cm) between the radioactive source and the tissue which is to receive radiotherapy. It should be noted however that brachytherapy is a comprehensive term, and includes radiotherapy effected by interstitial, intercavitary, and surface application (plaque). Interstitial and intracavitary techniques are particularly advantageous where deep-seated lesions are involved while plaque therapy is particularly advantageous where superficial or accessible diseased tissue is involved. In contrast, another form of radiation therapy, “external beam therapy”, involves treatment at relatively large distances (i.e., 50–500 cm) between the radiation source and the skin surface. Accordingly, with “external beam therapy,” it generally is difficult to mitigate damage to underlying disease yet spare the normal tissues which may be included in the path of the radiation towards the target. Recent approaches using intensity-modulated radiotherapy (See, e.g. Tsai, et al., 2000. Dependence of linac output on the switch rate of an intensity-modulated tomotherapy collimator, Med. Phys. 27).
There are two general types of brachytherapy, those involving permanent implants and those which utilize temporary implants. Although a wide variety of radioactive elements (“radioisotopes”) have been previously proposed for therapeutic use, only a relatively small number have actually been accepted and employed on a large-scale basis. This is due, at least in-part, to a relatively large number of constraining considerations where medical treatment is involved (i.e., the energy of the emitted radioactivity, half-life, availability, and the like). An element employed almost immediately after its discovery in 1898, was radium. Although radium possesses a long half-life (i.e., approximately 1600 years), a particularly undesirable property is the requirement for careful attention to the protection of medical personnel, as well as healthy tissue of the patient. This is due to its complex and highly penetrating gamma ray emission. To minimize exposure to medical personnel, specialized and sometimes complicated “after loading” techniques have been developed whereby the radioisotope is guided, for example through a hollow tube, to the treatment region following preliminary placement of the specialized appliances required.
More recently, permanent implants using radioactive “seeds” containing iodine-125 have been previously employed. Similarly, for temporary implants, cesium-137, iridium-192, and palladium-103 sources have been employed. These radionuclides will be briefly discussed, infra. In addition, the use of xenon-133 and xenon-131 have also be suggested.
In order to avoid harming the patient and to guarantee the requirements for accurate irradiation, the radioactive source(s) must be accurately positioned and fixed on or in the body. Only when this is ensured can programming of the required isodose contour take place and properly pre-planned irradiation be guaranteed. If the radiation source is not accurately positioned, there may be considerable overdosage to normal (i.e., non-tumorogenic) tissue, with serious risk of harm to the patient, or exposure of medical staff to radiation. See, e.g., Gosh, 1991. Sicherheitstechnisch bedeutsame Ereignisse an Afterloadinganlagen: Untersuchungen zur Strahlenexposition, Folgerungen zur Sicherheit von Personal und Patient [Events with relevance to safety in afterloading systems: Investigations on radiation exposure, consequences for safety of staff and patient] Diplomarbeit Berufsakademie, Karlsruhe. Additionally, in cases of repeated radiation treatments, where a reduced radiation dose is given in each subsequent treatment, accurate localization of the radioactive source(s) at the site of treatment over a lengthy period is of particular importance.
II. Radionuclides Traditionally Utilized in Brachytherapy
Initially, interstitial implants were performed with radium-226 (226Ra) needles. However, due to serious radiation safety considerations from the highly penetrating gamma-rays, this radioisotope has largely been replaced with other radionuclides. Currently, the vast majority of interstitial brachytherapy treatments in North America are done using either iridium-192 (192Ir), iodine-125 (125I), or cesium-137 (137Cs) sources. Recently, palladium-103 (103Pd) sources have also become available for permanent implants. A brief description of 192Ir, 125I, 137Cs, and 103Pd sources is given in the following sections.
1. Iridium-192 (192Ir) Sources
192Ir is produced when stable 191Ir (37% abundance) absorbs a neutron. 192Ir decays with a short 73.83 day half-life to several excited states of 192Pt and 192Os which are both gamma ray emitters with a varying range of energies. The average energy of the emitted photons from an unencapsulated source is approximately 0.4 MeV. In the United States, 192Ir is used for interstitial radiotherapy is usually in the form of small cylindrical sources or “seeds” which are from 3 to 10 mm long and approximately 0.5 mm in diameter.
2. Iodine-125 (125I) Sources
125I is produced when 124Xe absorbs a neutron, and then decays via electron capture. 125I itself decays with a half-life of only 59.4 days, by electron capture to the first excited state of 125Te, which subsequently undergoes internal conversion 93% of the time and otherwise emits a 35.5 keV gamma-ray. The electron capture and internal conversion processes give rise to characteristic x-rays. 125I for interstitial implants is available commercially in the form of small “seeds” of varying sizes and activities.
3. Palladium-103 (103Pd) Sources
103Pd is formed when stable 102Pd absorbs a neutron. It decays via electron capture, mostly to the first and second excited states of 103Rh with a 17.0 day half-life. De-excitation is almost totally via internal conversion, leading to the production of characteristic x rays. Average photon energy is approximately 21 keV. 103Pd sources are similar in size and encapsulation to those for 125I sources, typically being 4.5 mm long and 0.8 mm in diameter.
4. Cesium-137 (137Cs) Sources
137Cs possesses a half-life of 30 years. Gamma radiation from 137Cs has an energy of 662 keV, which in comparison to the other radionuclides in this section, is highly energetic.
III. Dose Formalisms in Brachytherapy (TG-43)
A large number of references have been published which introduce revised radiation sources, calibration standards, source strength specification quantities, and dose calculation formalisms for, e.g., 192Ir, 125I, and 103Pd sources. To promote accuracy and uniformity of clinical practice, the Radiation Therapy Committee of the American Association of Physicists in Medicine (AAPM) formed Task Group No. 43 (TG-43) to review publications on dosimetry of interstitial brachytherapy sources and recommend a dosimetry protocol which would include a formalism for dose calculations and a data set for the values of dosimetry parameters. See, Nath, et al., 1995. Dosimetry of interstitial brachytherapy sources: Recommendations of the AAPM Radiation Therapy Committee Task Group No. 43, Med. Phys. 22: 209–234). The TG-43 publication presented a formalism that clearly defined the necessary physical quantities (e.g., air kerma strength, radial dose function, anisotropy function, dose rate constant, and the like) for the calculation of accurate, quantitative dosimetric data.
Although the TG-43 protocol set forth dosimetric criteria for various interstitial brachytherapy sources, it failed to provide any dosimetric protocols for 252Cf, dealing instead only with 192Ir, 125I, and 103Pd radionuclides. Additionally, clinical data and experimental results have shown that specification of dose to muscle, rather than to water, is recommended for clinical dosimetry of 252Cf medical sources. This is in direct conflict with the recommendations of the TG-43 protocol since the kinetic energy released in matter (kerma) varies more between muscle and water for neutrons than for photons. Moreover, there are no reports which have: (i) formulated a 252Cf brachytherapy neutron dosimetry protocol which is similar to that set forth in the ICRU-45 protocol; (ii) quantitatively measured or calculated (using Monte Carlo methods) neutron or photon dose from various different 252Cf sources in a number of media using modern measurement techniques and apparatus or modern radiation transport codes with recent and accurate cross-section data; and (iii) compared these 252Cf dosimetry calculation to those previous reported. Accordingly, there remains an, as yet unfulfilled, need for an efficacious 252Cf brachytherapy dosimetry formalism which has utilized state-of-the-art methodologies in its derivation. Additionally, because 252Cf is the only feasible neutron-emitting radioisotope, there exists the unique possibility to enhance 252Cf brachytherapy with neutron capture therapy (NCT) using various neutron capture agents with relatively high neutron capture cross-sections such as, for example, 10B, 157Gd, 3He, 133Xe, or 135Xe.
IV. Encapsulation and Delivery of Radionuclide Sources in Brachytherapy
As of August 2000, there are no medical institutions within the United States using 252Cf sources for tumor therapy. Neutron brachytherapy (i.e., insertion of the neutron-emitting source directly into or around the tumor) is markedly more effective than conventional photon radiotherapy in treating certain tumors, specifically bulky tumors and hypoxic (oxygen-deficient) tumors. For example, impressive results have been reported using 252Cf brachytherapy for advanced bulky gynecological tumors. See, Maruyama, et al. 1991. A review of californium-252 neutron brachytherapy for cervical cancer, Cancer 68: 1189, and also see, Maruyama, et al., 1985. Clinical trial of 252Cf neutron brachytherapy vs. conventional radiotherapy for advanced cervical cancer, Int. J. Radiation Oncology, Biol. Phys. 11: 1475. In addition, a recent workshop presented data on improved survivability for several types of bulky and recurrent tumors (e.g., head and neck, gynecological, rectal) from 252Cf brachytherapy followed by photon therapy, compared with photon therapy alone. See, Wierzbicki, 1996. Californium-Isotope for 21st century radiotherapy, NATO Advanced Research Workshop, Detroit, Mich., Apr. 24–28, 1996.
Generally, clinicians only have available a 25-year-old brachytherapy source design developed at Savannah River Laboratory (SRL) called the Applicator Tube (AT), which was designed similarly to the popularly utilized “radium needles” of that time period. See, e.g., Maruyama, et al., Californium-252 neutron brachytherapy, in: Principles and Practices of Brachytherapy, edited by S. Nag (Futura, Armonak, N.Y. 1997) pp. 649–687. These sources may be manually “loaded” into the patient and require treatment times of several hours. The currently available 252Cf AT source geometry has an active length of 15 mm and is double-encapsulated in an alloy comprising of 90% mass platinum and 10% mass iridium (Pt/Ir-10%) which is 23 mm long and 2.8 mm in diameter as now fabricated at Oak Ridge National Laboratory (ORNL) in Tennessee. A schematic diagram of an ORNL-fabricated 252Cf AT source geometry 10 is illustrated in FIG. 1. The geometry 10 includes a core wire 12, a primary capsule 14, a secondary capsule 16, a Bodkin eyelet 18, and two tungsten-arc weld closures 20, 22. Exemplary materials include a Pd-DF oxide composite for the core wire 12, Pt-10%Ir for the primary capsule 14, and Pt-10%Ir for the secondary capsule 16. Unfortunately, this AT-type source is rather large and cumbersome for use in restricted brachytherapy treatment geometries (e.g., the virulent brain tumor glioblastoma multiforme). Also, typical catheter outer diameters exceed 5 mm. Thus, there remains an, as yet, unfulfilled need for the development of a 252Cf source which possesses both high activity and overall small size.